To evaluate selected biomarkers of tobacco exposure and biomarkers of harm and assess quality of life measures in smokers randomly switched from their usual brand of cigarette to one of three test products: (1) a tobacco-heating cigarette; (2) snus (smokeless tobacco); or (3) an ultra-low machine yield tobacco-burning cigarette.

A randomized, multi-center, 4-group study of health status measures and biomarkers in subjects who smoke and are switched to either a tobacco-heating cigarette, snus, or a tobacco-burning cigarette, with a non-treatment group of never-smokers.

Primary Objectives:

• Evaluate select biomarkers of tobacco exposure and biomarkers of harm from subjects who smoke and who are switched to a tobacco-heating cigarette, snus, or a tobacco-burning cigarette.
• Evaluate ability of a tobacco-heating cigarette and snus to modify patient-reported Chronic Obstructive Pulmonary Disease (COPD)-related health status in subjects who smoke and are switched to either a tobacco-heating cigarette or snus relative to a control group (a tobacco-burning ultra-low machine yield [ULMY]) cigarette.
• Assess subject compliance.

Secondary Objectives:

• Measure amount and repeatability of smoke components yielded from the cigarettes (yield in use) and determine relative uptake of selected smoke components.
• Evaluate the ability of a tobacco-heating cigarette and snus to modify general health status as measured by self-administered health questionnaires in subjects who smoke and are switched to either a tobacco-heating cigarette or snus relative to a control group (a tobacco-burning ULMY cigarette).
• Compare health status measures in smokers who are switched to a tobacco-heating cigarette to smokers who are switched to snus.
• Compare baseline data from all tobacco-using groups to baseline data from the never-smoking (non-treatment) group.

Inclusion Criteria:

• Males or females, between 28 and 55 years of age, inclusive.
• Cigarette-only smokers who currently smoked at least 15 cigarettes daily and who smoked for at least 10 years prior to Week 0 (i.e., chronic cigarette smokers).
• Smokers not intending to quit smoking, but willing to switch their tobacco product (intent to quit was defined as intending to make or making a quit attempt within 1 month prior to Week 0).
• Non-smoking subjects who self-reported "Never-Smoker" per the American Thoracic Society Questionnaire definition, and did not have urinary cotinine levels exceeding 50 ng/mL.
• Subjects, in the opinion of the Investigators, free of clinically significant health problems and not on medication on a daily basis for chronic medical disorders deemed clinically significant by the Investigator(s).
• Subjects not regularly taking creatine supplements.
• Subjects testing negative for selected drugs of abuse at Screening (included alcohol test).
• Subjects with a negative hepatitis panel (including hepatitis B surface antigen [HBsAg] and hepatitis C virus antibody [anti-HCV]) and negative Human Immunodeficiency Virus (HIV) antibody screens (for subjects immunized against hepatitis B with documentation of this immunization, a positive test result was not exclusionary).
• Female subjects who were non-pregnant (urine pregnancy test results were negative at Screening and Weeks 0, 12, and 24), non-lactating, and either postmenopausal (as verified by Follicle Stimulating Hormone levels) for at least 1 year, surgically sterile (e.g., tubal ligation, hysterectomy) for at least 90 days, or agreed to use from the time of signing the informed consent until 30 days after Week 24 (or Study Completion) a form of contraception considered acceptable to the Investigators (such as oral, injectable or implantable contraceptives, intrauterine devices and barrier methods ).
• Subjects able to read and comprehend questionnaires in English and willing to sign an Informed Consent Form.

Exclusion Criteria:

• Smokers using any other tobacco or nicotine-containing product or device other than tobacco-burning cigarettes from 6 months prior to the study through Week 24, including cigars, pipes, chewing tobacco, snuff, snus, nicotine patch, nicotine gum, etc.
• A history or clinical manifestations of significant metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, urological, neurological, or psychiatric disorders.
• A history of hypersensitivity or allergies to any drug compound unless approved by the Investigator(s).
• A history or presence of an abnormal ECG deemed clinically significant by the Investigator.
• A history of alcoholism or drug addiction within 1 year prior to Study Entry.
• Evidence of visible oral cancer, as found in an oral health examination or based on oral health questions at each visit.
• Any acute or chronic condition that, in the Investigator(s)' opinion, limited the subject's ability to complete and/or participate in the study.
• Donation of blood from 30 days prior to Screening through Week 24 (or Study Completion), inclusive, or plasma from 2 weeks prior to Screening through Week 24 (or Study Completion), inclusive.
• Receipt of blood products within 2 months prior to Study Entry.
• Subject or a relative of the subject was currently or had ever been employed by the tobacco industry.
• Subject participated in any other investigational study drug or product trial in which receipt of an investigational study drug or product occurred within 30 days prior to Check-in (inclusive).